3-diazine substituted benzothiadiazines

ABSTRACT

3-Diazine(or substituted diazine)-1,2,4-benzothiadiazine-1,1dioxide products or 3,4-dihydro derivatives thereof are described. Products are prepared by conventional methods employing the appropriate sulfamoylaniline and diazine carboxylic acid halide or diazine carboxaldehyde. Products are xanthine oxidase inhibitors.

United States Patent Novello 1 June 17, 1975 [5 3-DIAZINE SUBSTITUTED 3,095.446 6/1963 Margerison et a1 260/243 D BENZOTHIADIAZINES 3,351,595 11/1967 de Stevens ct a1 260/243 D [75] Inventor: Frederick C. Novello, Berwyn. Pa. Primary Examiner Nicholas S. Rizzo [73] Assignee: Merck & C0., lnc., R hw NJ, Attorney, Agent, or Firm-Daniel T. Szura; .1. Jerome B h R A .I 22 Filed: Mar. 20, 1972 e ddph J r [21] Appl. No.1 236,243 [57] ABSTRACT 3-Diazine(or substituted diazine)-1,2,4-benz0thiadia- 52] US. Cl. 260/243 D; 424/246 -lJ- i xi p c or -dihydro derivatives [51] Int. Cl C07d 93/34 thereof are s dr ducts are prepared by con- [58] Field Of Search 260/243 D ventional methods p y g the pp p famoylaniline and diazine carboxylic acid halide or di- 5 References Cited azine carboxaldehyde. Products are xanthine oxidase inhibitors.

7 Claims, N0 Drawings 1 S-DIAZINE SUBSTITUTED BENZOTHIADIAZINES This invention is concerned with b'enzo'thiadiazine compounds having a 3-diazine substituent which have been found to exhibit marked xanthine oxidase inhibiting properties equal to or greater than exhibited by allopurinol when all compounds are evaluated in the same in vitro test.

The novel products of this invention have the structural formula and pharmacologically acceptable salts thereof wherein R, R and R are similar or dissimilar groups selected from hydrogen and lower alkyl having from I to 5 carbon atoms, X is selected from halogen, particularly chloro or bromo, trifluoromethyl, and lower alkyl having advantageously from I to 3 carbon atoms and R is a diazine attached through one of its carbon atoms to the benzothiadiazine nucleus and optionally monoor di-substituted with similar or dissimilar groups selected from C alkyl, halo, advantageously chloro and bromo, lower alkoxy and hydroxy. The diazine substituent is derived from a pyrazine, pyridazine o9 pyrimiuine and attachment to the benzothiadiazine nucleus can be through any of the available carbons of the diazine nucleus.

The products of this invention can be prepared by one or another of the well known procedures for making benzothiadiazine compounds of structure I or 3,4-dihydrobenzothiadiazine compounds of structure II.

In general, the benzothiadiazine compounds of structure l can be prepared by reacting a mixture of the appropriate orthanilamide derivative with the heterocyclic acid halide which, for practica] purposes, can be the acid chloride. The acid chloride can be preformed and employed in the reaction or it can be prepared in situ by the addition of phosphorus oxychloride to a mixture of the orthanilamide and the heterocyclic carboxylic acid. When the acid chloride is preformed, the reaction advantageously is conducted in the presence of an inert solvent such as dioxane, tetrahydrofuran, dimethylformamide, and the like and is facilitated by heating up to the reflux temperature of the reaction mixture. When the heterocyclic acid chloride is formed in situ, the phosphorus oxychloride serves not only to form the acid chloride but as solvent as well.

A conventional method for preparing the 3,4-dihydrobenzothiadiazine of structure ll above comprises reacting a mixture of the appropriate orthanilamide derivative with the heterocyclic aldehyde, generally in the presence of a mineral acid. In those instances where a substituent is attached to either the heterocyclic moiety or the orthanilamide moiety that would be removed under acid conditions the reaction can take place in the presence of base such as an alkali metal hydroxide or the reaction time in the presence of a mineral acid can be closely followed to determine the point at which cyclization is effected. When acid labile groups are preseat the reaction generally is conducted at ambient temperature in the presence of mineral acid. When an alkali metal hydroxide is employed or when no acid labile groups arepresent the reaction mixture can be heated up to reflux conditions. It is well known that the 3,4- dihydro compounds (II) can be prepared from the hydro compounds (I) by reduction employinghydroge nation in the presence of ruthenium or by treatment with an alkali metal borohydride or an equivalent reducing agent capable of reducing the double bond.

Various methods of reducing the double bond have been described in the literature and any one of these methods can be employed in converting the products of structure I to he products of structure II.

Pharmacologically acceptable salts generally are the alkali metal salts which may be prepared by conventional methods, for example by treatment with an alkali metal hydroxide, e.g. sodium or potassium hydroxide, in a solvent such as a lower alkanol or in water and evaporating the solvent or by reacting the free compound, for example, in an ether, e.g. p-dioxane' or diethyleneglycol dimethyl ether solution with an alkali metal hydride or amide and removing the solvent. Monoor poly-salts may be obtained.

The novel products of this invention are effective inhibitors of xanthine oxidase, in decreasing the concentration of uric acid in the blood and urine, and in increasing the excretion of hypoxanthine and xanthine. The products are therefore useful in the treatment and management of gout preferably by oral administration of from about I00 to 800 mg, perday in divided doses as prescribed by the physician.

The following methods were employed to prepare the products of Table I.

METHOD A A mixture of the orthanilamide derivative (0.02 mole) and heterocyclic acid chloride (0.022 mole) in ml. of dioxane or other inert organic solvent is heated under reflux conditions for about 24 hours. The mixture is chilled, the solid collected, washed with cold ether and dissolved in a mixture of 75 ml of ethanol and 75 ml. of concentrated ammonium hydroxide. The

, solution is heated under reflux for three hours, then concentratedto dryness in vacuo, the residue suspended in ml. of water and the product precipitated upon acidification with hydrochloric acid. The product is purified by recrystallization from a mixture of dimethylformamide and water.

METHOD B I nol and 50 ml. of concentrated ammonium hydroxide for two hours. After concentration in vacuo, the residue is treated with 50 ml. of water and the product separated by acidification with hydrochloric acid.

METHOD C A solution of the appropriate orthanilamide derivative (0.01 mole) and heterocyclic aldehyde (0.01 1 mole) in 60 ml. of water, 2 ml. of ethanol and 1.5 ml.

' zine-1,1-dioxide (prepared as described in Example 6) Analysis calculated for C H N O S C, 40.78; H, 3.14; N. 19.82; Found: C, 40.74; H, 3.27; N, 19.49.

The general methods employed for preparing the 3,4-dihydrobenzothiadiazine compounds are described in the following Methods C-E.

The products i f fi were prfepafed by the prose 5 of concentrated hydrochloric acid is heated under re dure ofMethod f B asmdlcated m table flux for 2 hours. The hot mixture is filtered and the c bd g ig lf a L m product purified by recrystallization from a mixture of boxy 1c acl or aci ar e avrng t e substituents es- 7 dimethylformamide and water lgnated 1n the table. The substituents X, R, R and R 1 of the starting materials appear unchanged in the end 10 METHOD D P A solution of the appropriate orthanilamide deriva- 2% x NH 2 3 x %'-R l R -COR -e l RR N023 SOZNHZ RR N025 051%! Meth ANALYSIS Ex 1 mp. of Calculated Found No X R R' R2 R" C. Syn. Formula C H N C H N 1 C1 CH CH pyrazinyl C1 259-60 A C, H .,ClN -,O.,S 44.59 4.40 15.29 44.86 4.36 15.06

2 C1 H H pyrazinyl C1 360 A H,.C11 1,,O..S 35.34 2.16 18.74 35.19 2.15 18.79

3 Cl H H Z-methylpyrazin-S-yl Cl 360 B C,- ,H111CIN I,O.,S. 37.16 2.60 18.06 37.5) 2.71 17.83

4 C1 H H pyridazin-4-yl OH 360 B C ,H,.ClN -,O S 35.34 2.16 18.74 35.22 2.49 19.03

5 CF H H pyridazin-4yl OH 360 B 35.38 1.98 17.19 35.51 2.17 16.89

6 CH H H 3-Cl-pyridazin-6-yl OH 350 B C, l 1..lClN, O..S 37.16 2.60 18.06 36.68 2.66 17.70

7 C1 H H 6-Cl-3-OH-pyridazin-4-yl OH 350 B C,,H Cl-,N,,O .,S 31.14 1.66 16.51 30.67 1.71 16.17

8 Cl H H pyrimidin-4-yl OH 360 B C,,H,.C1N -,O,,s 35.34 2.16 18.74 35.68 2.32 18.61

9 CF H H pyrimidin-4-yl OH 325-27 B C,. .H,.F.,N -,O..s 35.38 1.98 17.19 35.54 2.02 17.24

10 Cl H H pyrimidln2-yl OH 360 B C, H, ClN -,O ,S 35.34 2.16 18.74 35.54 2.13 18.54 11 CH H H pyrimidin-4-yl OH 360 B C. H.,1-1 .,O ,S 40.78 3.14 19.82 40.65 3.27 19.45 12 Cl H H 2.6-(OH)rpyrimidin-4-yl OH 350 A C.,H,.C1N,,0.;s 32.56 1.99 17.26 33.18 1.92 17.29

EXAMPLE 13 35 tive (0.005 mole) and heterocyclic aldehyde (0.006

. mole in 22.5 ml. of ethanol a d a solut' f 90 1 6-Methyl-3-(pyr1daz1n-3-yl)-7-sulfamoyl-l,2,4- n Ion 0 mg I benzothiadiazine l l dioxide of sodium hydroxlde in 2.5 ml. of water is heated under V reflux for 3 hours, cooled and filtered. The product is A solution of 1.2 g. (0.003 mole) of 6-methyl-3(3'- precipitated'from the filtrate upon acidification with chloro-6'-pyridazinyl)-7-sulfamoyl-1,2,4-benz0thiadia- 4Q hydrochloric acid and then purified by recrystallization from a mixture of dimethylformamide and water.

METHOD E A solution of the appropriate orthanilamide derivative (0.01 mole) and heterocyclic aldehyde (0.02 mole) in ml. of ethanol and 20 ml. of 6N hydrochloric acid is stirred at room temperature for 1 hour. The resulting solid is collected by filtration and purified by recrystallization from a mixture of dimethylformamide and water.

The substituents attached to the orthanilamide and heterocyclic aldehyde reactants as well as the end product, structure 11, are identified in Table 11 along with the melting point and analysis for the end product obtained by the method of synthesis specified.

TABLE II N H 2 x N11 x R l R-cno '-9 l 1 I l 4 l l 1 L '2 RR NO S SO NJR RR NO SV EW 1 Melh ANALYSlS Ex m.p of Calculated Found No X R R" R R4 C. Syn. Formula C ;H N C H N 14 CI H H Z-methoxypyrazin-S-yl H 270-71 C .H,. .ClN -,O -,S- 35512.98 17.26 35.88 3.03 17.16 15 (1 H H pyrazinyl H 228-29 C C,.H,1,CIN -,O..S- 35.15 2.68 18.64 34.92 2.69 18.67 16 CI H H Z methnXypyrazin-S-yl CH 233- C (,;,H .(l;' 1 -,S 37.1) 3.36 16.68 37.41 3.30 16.71

Table II (ontinued Meth ANALYSIS Ex m.p. of Calculated Found No X R R R R C. 'n. Formula C H N C H N 1'! (1 H H 2-HU-p ,'rtmn-5- H 360 L (11H111CIN505S2 33.72 2.57 17.88 33.94 2.87 17.54 114 (1 H H Z-ethoxypyrumn-S-yl H 231-33 D C,;,H C1N,-,O -,S 37.19 3.36 16.68 37.55 3.42 16.62 19 ('1 H H 2-propoxypyrazin-5-y1 CH 234-37 F -,H ,.C1N -,O -,S 40.22 4.05 15.64 40.44 4.06 15.65 20 (1 H H Z-HO-pyruzimS-yl CH 274-76 E C H Cl 0 8;, 35.51 2.98 17.26 35.55 3.05 17.12 2l (l H H 2-ethoxypyraxin-5-y1 (H l7XX0 F C H .;ClN -,O;,S 38.75 3.72 10.14 39.09 3.89 loll 22 ('1 H H 2-mcthylpyruzm-5-yl CH 24748 F C H .,C1N,-,O,,S- 38.66 3.49 17.34 39.20 3.69 17.25 23 (l H H 2-pentyloxypyrnzin-S-yl CH 215-17 C -H ,(1N -,O -,S 42.90 4.66 14.71 43.11 4.74 14.58

EXA LE 24 and pharmacologically acceptable salts thereof wherein R is hydrogen or C alkyl; R is hydrogen or 15 C alkyl, R is pyridazinyl or a substituted pyridazinyl derivative wherein the substituent is one or two similar or dissimilar groups selected from C alkyl, lower alkoxy, hydroxy, chloro and bromo; R is hydrogen or C alkyl; and X is halo, C alkyl and trifluoromethyl. 2O 2. A product as claimed in claim 1 wherein R is pyridazinyl.

3. A product as claimed in claim 2 wherein R and R are each hydrogen, X is chloro and R is 4-pyridaziny1. 4. A product as claimed in claim 2 wherein R and R 25 are each hydrogen, X is trifluoromethyl and R is 4- pyridazinyl.

5. A product of claim 1 wherein R is substituted 2 pyridazinyl. I l R 6. A product of claim 5 wherein X is methyl, R, R

are each hydrogen and R is 3-Cl-pyridazin-6-yl. 7. A product of claim 5 wherein X is chloro, R and R are each hydrogen and R is 6-chloro-3- hydroxypyridazin-4-y1.

6-Chloro-2-methyl-3-( pyrimidin-4-yl )-7-sulfamoy1-3,4- dihydro- 1 ,2,4-benzothiadiazine-l ,1 -di0xide This product is prepared by reacting Z-(N- methylsulfamoyl)-4-sulfamoyl-5-chloro aniline and pyrimidine aldehyde-4-diethylaceta1 according to the procedure of Method E.

What is claimed is: l. A benzothiadiazine having the structure 

1. A BENZOTHIADIAZINE HAVING THE STRUCTURE
 2. A product as claimed in claim 1 wherein R2 is pyridazinyl.
 3. A product as claimed in claim 2 wherein R and R1 are each hydrogen, X is chloro and R2 is 4-pyridazinyl.
 4. A product as claimed in claim 2 wherein R and R1 are each hydrogen, X is trifluoromethyl and R2 is 4-pyridazinyl.
 5. A product of claim 1 wherein R2 is substituted pyridazinyl.
 6. A product of claim 5 wherein X is methyl, R, R1 are each hydrogen and R2 is 3-Cl-pyridazin-6-yl.
 7. A product of claim 5 wherein X is chloro, R and R1 are each hydrogen and R2 is 6-chloro-3-hydroxypyridazin-4-yl. 